A multicenter study led by Memorial Sloan Kettering Cancer Center investigators concluded that treatment with a new targeted therapy called PLX4032 resulted in significant tumor shrinkage in 80 percent of patients with advanced melanoma.

“We never before had a specific target in melanoma that we could attack,” said Memorial Sloan Kettering medical oncologist Paul B. Chapman, senior author of the study, published in the New England Journal of Medicine. [PubMed Abstract] “But we now know half of melanomas depend on a mutated gene called BRAF for their growth. PLX4032 inhibits BRAF at the cellular level and shuts off these tumors. We have seen many tumors shrink rapidly and, in some patients, quality of life improved dramatically.”

The phase I trial determined the maximum dose of the drug that could be given without adverse side effects and was followed by an extension of the trial, a phase II trial, at that recommended dose. Fifty-five patients were enrolled in the first portion of the study. Screening for BRAF mutations was not a requirement for initial entry, but as the trial progressed, an increasing percentage of patients were identified as having the mutation. Later, 32 patients with BRAF-mutated melanomas were added to the second phase.

In the phase I group, ten partial responses and one complete response were noted among 15 melanoma patients with BRAF mutations who were treated with moderate to full doses of the drug. In the extension group, two complete and 24 partial responses were seen among the 32 patients treated with a full dose of drug. To date, 16 of 32 patients are still in the study. The side effects were minor and did not result in any patients leaving the study.

Dr. Chapman is now leading a phase III trial of PLX4032, which completed accrual extremely quickly, in less than a year. “While we see most tumors shrink, the tumor responses are not always long-lasting,” he explained. “We don’t yet know if treatment improves overall survival of melanoma patients. However, our new understanding of the molecular pathways driving melanoma provides a strong rationale to combine PLX4032 with other new antimelanoma drugs.”